Prithvi Shiva-Kumar

Effect of Inorganic Nitrate on Exercise Capacity in Heart Failure With Preserved Ejection Fraction

Background— Inorganic nitrate (NO3−), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide in the setting of hypoxia. We tested the hypothesis that NO3− supplementation improves exercise capacity in heart failure with preserved ejection fraction via specific adaptations to exercise. Methods and Results— Seventeen subjects participated in this randomized, double-blind, crossover study comparing a single dose of NO3-rich beetroot juice (NO3−, 12.9 mmol) with an identical nitrate-depleted placebo. Subjects performed supine-cycle maximal-effort cardiopulmonary exercise tests, with measurements of cardiac output and skeletal muscle oxygenation. We also assessed skeletal muscle oxidative function. Study end points included exercise efficiency (total work/total oxygen consumed), peak O2, total work performed, vasodilatory reserve, forearm mitochondrial oxidative function, and augmentation index (a marker of arterial wave reflections, measured via radial arterial tonometry). Supplementation increased plasma nitric oxide metabolites (median, 326 versus 10 &mgr;mol/L; P=0.0003), peak O2 (12.6±3.7 versus 11.6±3.1 mL O2·min−1·kg−1; P=0.005), and total work performed (55.6±35.3 versus 49.2±28.9 kJ; P=0.04). However, efficiency was unchanged. NO3− led to greater reductions in systemic vascular resistance (−42.4±16.6% versus −31.8±20.3%; P=0.03) and increases in cardiac output (121.2±59.9% versus 88.7±53.3%; P=0.006) with exercise. NO3− reduced aortic augmentation index (132.2±16.7% versus 141.4±21.9%; P=0.03) and tended to improve mitochondrial oxidative function. Conclusions— NO3− increased exercise capacity in heart failure with preserved ejection fraction by targeting peripheral abnormalities. Efficiency did not change as a result of parallel increases in total work and O2. NO3− increased exercise vasodilatory and cardiac output reserves. NO3− also reduced arterial wave reflections, which are linked to left ventricular diastolic dysfunction and remodeling. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT01919177.

Effective Arterial Elastance Is Insensitive to Pulsatile Arterial Load

Effective arterial elastance (EA) was proposed as a lumped parameter that incorporates pulsatile and resistive afterload and is increasingly being used in clinical studies. Theoretical modeling studies suggest that EA is minimally affected by pulsatile load, but little human data are available. We assessed the relationship between EA and arterial load determined noninvasively from central pressure–flow analyses among middle-aged adults in the general population (n=2367) and a diverse clinical population of older adults (n=193). In a separate study, we investigated the sensitivity of EA to changes in pulsatile load induced by isometric exercise (n=73). The combination of systemic vascular resistance and heart rate predicted 95.6% and 97.8% of the variability in EA among middle-aged and older adults, respectively. EA demonstrated a quasi-perfect linear relationship with the ratio of systemic vascular resistance/heart period (middle-aged adults, R=0.972; older adults, R=0.99; P<0.0001). Aortic characteristic impedance, total arterial compliance, reflection magnitude, and timing accounted together for <1% of the variability in EA in either middle-aged or older adults. Despite pronounced changes in pulsatile load induced by isometric exercise, changes in EA were not independently associated with changes pulsatile load but were rather a nearly perfect linear function of the ratio of systemic vascular resistance/heart period (R=0.99; P<0.0001). Our findings demonstrate that EA is simply a function of systemic vascular resistance and heart rate and is negligibly influenced by (and insensitive to) changes in pulsatile afterload in humans. Its current interpretation as a lumped parameter of pulsatile and resistive afterload should thus be reassessed.

Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction

Background Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. Methods and Results We randomized 44 patients with heart failure with preserved ejection fraction in a double‐blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6‐minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14–0.17], 3 months=0.11 [95% CI, 0.10–0.13], 6 months=0.10 [95% CI, 0.08–0.12] mm Hg/mL per second; P=0.003) and forward wave amplitude (Pf, mean baseline=54.8 [95% CI, 47.6–62.0], 3 months=42.2 [95% CI, 33.2–51.3]; 6 months=37.0 [95% CI, 27.2–46.8] mm Hg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35–0.43]; 3 months=0.31 [95% CI, 0.25–0.36]; 6 months=0.44 [95% CI, 0.37–0.51], P=0.03), reduced 6‐minute walk distance (mean baseline=343.3 [95% CI, 319.2–367.4]; 6 months=277.0 [95% CI, 242.7–311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7–1029.7]; 6 months=1054.5 [95% CI, 1036.5–1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007). Conclusions ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction. Clinical Trial Registration URL: www.clinicaltrials.gov. Unique identifier: NCT01516346.

TIME-RESOLVED LEFT VENTRICULAR MYOCARDIAL STRESS IN HEART FAILURE WITH REDUCED EJECTION FRACTION REVEALS A MARKED INCREASE IN LATE SYSTOLIC MYOCARDIAL LOAD

Systolic myocardial wall stress (MWS) quantifies myocardial afterload. Despite its time-varying nature, little data exist regarding time-resolved MWS in systolic heart failure (HF). We studied 10 subjects with systolic HF (mean LV ejection fraction=40%). We assessed time-resolved LV volume and